Pharmaceutical preparations

ABSTRACT

Pharmaceutical preparations containing glycerol alkyl ethers as the solvent.

BACKGROUND OF THE INVENTION

The solvents hitherto proposed and used for pharmaceutical preparationsare not entirely satisfactory in view of their various properties, forexample the dissolving power, the miscibility with other solvents andespecially the physiological compatibility. The disadvantages of suchcommercial pharmaceutical solvents are described, for example, in GermanAuslegeschrift No. 2 708 419. In said Auslegeschrift there are describedthe advantageous properties of 1,2-butanediol 1-methyl ether as thesolvent for pharmaceutical purposes. It has, meanwhile, been establishedthat this compound produces changes in the blood.

SUMMARY OF THE INVENTION

It has now been found in accordance with the present invention thatglycerol lower-alkyl ethers are especially suitable solvents forpharmaceutical purposes since they exhibit a very good dissolving power,are miscible with other pharmaceutical solvents and have a betterphysiological compatibility than 1,2-butanediol 1-methyl ether.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to pharmaceutical preparationscontaining a glycerol lower-alkyl ether as the solvent. The invention isalso directed to the use of lower-alkyl ethers as the solvent inpharmaceutical preparations. This invention is especially adapted topreparing injectable solutions containing a pharmaceutically-activeingredient.

The term "lower alkyl" as used in this application designates straight-or branched-chain saturated aliphatic hydrocarbon groups containing from1 to 7 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, t-butyl, etc.

In accordance with this invention, the pharmaceutical preparationscontain a pharmaceutically-active ingredient and a solvent containing aglycerol lower-alkyl ether.

In accordance with this invention, any conventionalpharmaceutically-active ingredient which is soluble in a glycerollower-alkyl solvent can be utilized to prepare the pharmaceuticalpreparations.

Glycerol mono(lower-alkyl) ethers and glycerol di(lower-alkyl) ethersare especially suitable for the purpose of the present invention.Examples of such ethers are glycerol 1-methyl ether, glycerol 1-ethylether, glycerol 1,2-dimethyl ether and glycerol 1,3-dimethyl ether.Glycerol 1-methyl ether, glycerol 1,3-dimethyl ether and, especially,glycerol 1,2-dimethyl ether are particularly preferred.

Among the pharmaceutically-active ingredients contained in thepharmaceutical preparations of this invention are sulphonamides, forexample sulphamethoxazole, sulphadoxine, sulphamoxole or sulphathiazine;conveniently in the form of pharmaceutically-acceptable salts;sulphonamide potentiators, for example trimethoprim or diaveridine;benzodiazepines, for example diazepam, oxazepam or chlordiazepoxide; orvitamins, for example vitamin A acetate, vitamin K₁ or vitamin E. Ofparticular interest are pharmaceutical preparations which containsulphamethoxazole, trimethoprim and glycerol 1-methyl ether or diazepamand glycerol 1,1-dimethyl ether.

The solvent can be 100% by volume of the glycerol lower-alkyl ether.Generally, it is preferred that the solvent contain at least 50% byvolume of the glycerol lower-alkyl ether. The solvent can contain othercompatible ingredients such as water or ethanol. Among the preferredsolvents are those which contain from about 50% to 80% by volume of theglycerol lower-alkyl ether and from about 20% to 50% by volume of water.Among the other preferred solvent mixtures are those containing fromabout 50% to 80% by volume of the glycerol lower-alkyl ether, 20% to 50%by volume of water and 5% to 10% by volume of ethanol. Furthermore, ithas been found that in the case of pharmaceutical preparations whichhave a high water content and which contain an active substancedifficultly soluble in water, the stability during storage can beimproved when said preparations are heated for a short time (e.g., at120° C. for 10 minutes).

The pharmaceutical preparations provided by the present invention can bemanufactured by dissolving a pharmaceutically-active substance in aglycerol lower-alkyl ether, if desired, with the addition of water orwater and ethanol.

The pharmaceutical preparations provided by the present invention areespecially suitable for use as injection solutions; for example, for theintravenous or intramuscular administration of pharmaceutically-activesubstances.

The following examples illustrate the present invention:

EXAMPLE 1

1 g of sulphamethoxazole is dissolved in 1 ml of 4 N sodium hydroxidewhile warming slightly. 0.2 g of trimethoprim in 3.5 ml of glycerol1-methyl ether is added to this solution while stirring, a clearsolution resulting. If desired, this solution is filtered sterile andfilled into ampoules.

EXAMPLE 2

10 mg of diazepam are dissolved in 1.2 ml of glycerol 1,2-dimethylether. The solution is treated with 0.8 ml of water and, if desired,filtered sterile and filled into ampoules.

EXAMPLE 3

10 mg of diazepam are dissolved in 1.5 ml of glycerol 1-methyl ether.The solution is mixed with 0.5 ml of water and, if desired, filteredsterile and filled into ampoules.

EXAMPLE 4

10 mg of diazepam are dissolved in 1.2 ml of glycerol 1-ethyl ether. Thesolution is mixed with 0.8 ml of water and, if desired, filtered sterileand filled into ampoules.

EXAMPLE 5

15 mg of vitamin A acetate are dissolved in 1 ml of glycerol 1-methylether. If desired, the solution is filtered sterile and filled intoampoules.

EXAMPLE 6

200 mg of vitamin K₁ are dissolved in 1 ml of glycerol 1,2-dimethylether. If desired, the solution is filtered sterile and filled intoampoules.

EXAMPLE 7

200 mg of vitamin E are dissolved in 1 ml of glycerol 1,2-dimethylether. If desired, the solution is filtered sterile and filled intoampoules.

EXAMPLE 8

1 g of sulphamethoxazole is dissolved in 1 ml of 4 N sodium hydroxidewhile warming slightly. To this solution is added with good intermixing0.2 g of trimethoprim in 3.05 ml of glycerol 1-methyl ether and 0.45 mlof rectified alcohol, there being obtained a clear solution.

EXAMPLE 9

1 g of sulphadoxine is dissolved in 1 ml of 3.3 N sodium hydroxide whilewarming slightly. To this solution is added with good intermixing 0.2 gof trimethoprim in 3.05 ml of glycerol 1-methyl ether and 0.45 ml ofrectified alcohol, there being obtained a clear solution.

EXAMPLE 10

10 mg of diazepam are dissolved in 0.9 ml of glycerol 1,2-dimethyl etherand 0.1 ml of rectified alcohol and treated with good intermixing with 1ml of physiological sodium chloride solution. A clear solution isobtained.

EXAMPLE 11

10 mg of diazepam are dissolved in 0.8 ml of glycerol 1,3-dimethyl etherand 0.1 ml of rectified alcohol and treated with good intermixing with1.1 ml of physiological sodium chloride solution. A clear solution isobtained.

EXAMPLE 12

10 mg of diazepam are dissolved in 0.9 ml of glycerol 1-ethyl ether and0.1 ml of rectified alcohol and combined with 1.0 ml of physiologicalsodium chloride solution to give a clear solution.

EXAMPLE 13

10 mg of diazepam are dissolved in 1.0 ml of glycerol 1-methyl ether and0.1 ml of rectified alcohol and mixed with 0.9 ml of physiologicalsodium solution to give a clear solution.

EXAMPLE 14

15 mg of vitamin A acetate are dissolved in 1 ml of glycerol 1-methylether at room temperature, there being obtained a clear solution.

EXAMPLE 15

200 mg of vitamin K₁ are dissolved in 1 ml of glycerol 1,2-dimethylether, there being obtained a clear solution.

EXAMPLE 16

200 mg of tocopherol are dissolved in 1 ml of glycerol 1,2-dimethylether, there being obtained a clear solution.

What is claimed is:
 1. A pharmaceutical preparation comprising aneffective amount of a benzodiazepine and a solvent containing glycerollower-alkyl ether, said glycerol lower-alkyl ether and said solventbeing present in an amount sufficient to dissolve said activeingredient.
 2. The preparation of claim 1 wherein said ether is presentin said solvent in an amount of at least 50% by volume.
 3. Thepreparation of claim 2 wherein the glycerol lower-alkyl ether is aglycerol mono(lower-alkyl)ether or a glycerol di(lower-alkyl)ether. 4.The preparation of claim 3 wherein the glycerol lower-alkyl ether isglycerol 1,2-dimethyl ether, glycerol 1-methyl ether or glycerol1,3-dimethyl ether.
 5. The preparation of claim 2 wherein the solventcontains 50% to 80% by volume of a glycerol lower-alkyl ether and 20% to50% by volume of water.
 6. The preparation of claim 5 wherein saidsolvent contains ethanol.
 7. The preparation of claim 6 wherein theactive ingredient is diazepam and the solvent is glycerol 1,2-dimethylether.